Approximately 400,000 germ cells are stored in the ovaries of the human female at the time of puberty. No further germ cells are made. Beginning at the time of puberty and ending at the menopause, there are approximately 400 ovulatory menstrual cycles which consume essentially all of the germ cells in the human ovary. About 1,000 germ cells are consumed in each menstrual period. However, in any one menstrual cycle only one germ cell, developed in what becomes the dominant follicle, is ovulated and available for pregnancy.
Human reproduction is extraordinarily inefficient. In spite of normal exposure to pregnancy, the probability of a normal pregnancy is no more than 25% during any one month. Thus, three times out of four either the ovulated germ cell is not fertilized (this is very rare) or the fertilized germ cell does not implant because of abnormalities of one kind or another or if it does implant, does not develop and is aborted.
Although the details are not accurately known, the mechanism by which a single egg each month is selected to become the dominant egg is dependent upon a complex interaction between one or more secretions from the ovary and at least two pituitary glycoprotein hormones, the follicular stimulating hormone (FSH) and the luteinizing hormone (LH). While there are undoubtedly numerous intermediates, particularly products of the central nervous system, the growth of several follicles in any one cycle is under the control of the pituitary gonadotropins, particularly FSH. The final maturation process for the egg resulting in its ovulation seems to be under the control of LH.
For more than twenty years, it has been possible to induce ovulation and menstruation, and sometimes pregnancy, in patients whose ovulatory mechanism is deranged so that normal cyclic ovulation and menstruation does not occur, by the administration of suitable amounts of a 50--50 mixture of FSH and LH known as human menopausal gonadotropin (hMG).
Normally menstruating women of reproductive age are many times rendered infertile by a variety of causes which cannot be corrected by endocrinological or surgical therapy. One example of such a difficulty is related to the bilateral removal of fallopian tubes for various causes such as sequential bilateral ectopic pregnancies. Under this circumstance, it has been shown that it is possible to harvest an egg from the dominant follicle using the natural cycle, provided this egg is harvested just prior to anticipated ovulation as determined by a measurement of the levels of LH, either in the serum or in the urine. Fertilization of this egg in vitro can be achieved in approximately 80% of the patients from which an egg can be obtained. Development to the 6-8 cell stage can be achieved in some 90% of the situations where the egg has been fertilized and if transferred to the donor of the egg, pregnancy will result in less than 15% of patients so treated in the natural cycle.
It is furthermore shown that the pregnancy rate will improve if more than one egg can be matured and harvested in any one menstrual cycle. This has been accomplished by a variety of techniques including the use of human menopausal gonadotropin according to a standard regime in a normally menstruating woman. In this way, more than a single egg can be matured and harvested in a single menstrual cycle. If one mature egg is so recruited the pregnancy rate is 20%; if two mature eggs are harvested, successfully fertilized, and transferred, the probability of pregnancy increases to 27%, and if three eggs can be successfully harvested, fertilized, and transferred, the pregnancy rate will increase to 38%, an improvement almost equal to 100% of that obtained with the transfer of a single egg. Table I demonstrates that using human menopausal gonadotropin, it is seldom possible to recruit three mature eggs.
TABLE I ______________________________________ PREOVULATORY EGG TRANSFERS (n = 272) # Eggs Occurrence % # Preg % Preg ______________________________________ 1 137 50.4 28 20.4 2 99 36.4 27 27.3 3 21 7.7 8 38.1 4 10 3.7 4 40.0 5 3 1.1 0 0 6 2 0.7 1 50.0 ______________________________________
In addition, there are some patients who are relatively refractory to hMG stimulation so that overall more than 20% of patients so stimulated fail to have a transfer of even one fertilized egg. Table II below shows that over 485 cycles, stimulation by human menopausal gonadotropin resulted in 367 transfers. Among these transfers, it was possible to recruit, fertilize and transfer two mature eggs in 131 of 367 transfers, or 38%, and it was possible to recruit, fertilize, and transfer the ideal number of three eggs only 61 of 367 times, or 16%.
TABLE II ______________________________________ TRANSFERS AFTER hMG TREATMENT (n = 367) # Eggs Occurrence % # Preg % Preg ______________________________________ 1 137 37.3 26 19.0 2 131 35.7 31 23.7 3 61 16.6 18 29.5 4 23 6.3 6 26.1 5 9 2.5 2 22.2 6 6 1.6 3 50.0 ______________________________________
It is the object of this invention is to provide and improve the method of oocyte recruitment so that it will be possible in an increased proportion of patients to recruit eggs and in these, to recruit more mature fertilizable oocytes and thus increase the pregnancy rate over that which is possible by the recruitment of a single mature egg.